Flavonoids--food sources and health benefits

Abstract

Flavonoids are a group of bioactive compounds that are extensively found in foodstuffs of plant origin. Their regular consumption is associated with reduced risk of a number of chronic diseases, including cancer, cardiovascular disease (CVD) and neurodegenerative disorders. Flavonoids are classified into subgroups based on their chemical structure: flavanones, flavones, flavonols, flavan-3-ols, anthocyanins and isoflavones. Their actions at the molecular level include antioxidant effects, as well the ability to modulate several key enzymatic pathways. The growing body of scientific evidence indicates that flavonoids play a beneficial role in disease prevention, however further clinical and epidemiological trials are greatly needed. Among dietary sources of flavonoids there are fruits, vegetables, nuts, seeds and spices. Consumption of these substances with diet appears to be safe. It seems that a diet rich in flavonoids is beneficial and its promotion is thus justifiable.

Full text

Rocz Panstw Zakl Hig 2014;65(2):79-85
*Corresponding author: Dorota Szostak-Węgierek, Zakład Żywienia Człowieka, Warszawski Uniwersytet Medyczny,
ul. Ciołka 27, 01-445 Warszawa, tel. +48 22 8360913,
e-mail: dorota.szostak-wegierek@wum.edu.pl
© Copyright 2013 by the National Institute of Public Health - National Institute of Hygiene
FLAVONOIDS - FOOD SOURCES AND HEALTH BENEFITS
Aleksandra Kozłowska1, Dorota Szostak-Węgierek2*
1 Department of Preventive Medicine and Hygiene, Institute of Social Medicine, Medical University of Warsaw, Poland
2 Department of Human Nutrition, Faculty of Health Science, Medical University of Warsaw, Poland
ABSTRACT
Flavonoids are a group of bioactive compounds that are extensively found in foodstuffs of plant origin. Their regular con-
sumption is associated with reduced risk of a number of chronic diseases, including cancer, cardiovascular disease (CVD)
and neurodegenerative disorders. Flavonoids are classified into subgroups based on their chemical structure: flavanones,
flavones, flavonols, flavan-3-ols, anthocyanins and isoflavones. Their actions at the molecular level include antioxidant
effects, as well the ability to modulate several key enzymatic pathways. The growing body of scientific evidence indicates
that flavonoids play a beneficial role in disease prevention, however further clinical and epidemiological trials are greatly
needed. Among dietary sources of flavonoids there are fruits, vegetables, nuts, seeds and spices. Consumption of these sub-
stances with diet appears to be safe. It seems that a diet rich in flavonoids is beneficial and its promotion is thus justifiable.
Key words: flavonoids, cancer, cardiovascular diseases, neurodegenerative disorders
STRESZCZENIE
Flawonoidy to grupa związków bioaktywnych występujących powszechnie w żywności pochodzenia roślinnego. Aktualne
dane literaturowe wskazują, że substancje te, spożywane wraz z dietą człowieka, wykazują działanie ochronne przed wie-
loma chorobami przewlekłymi, w tym przed niektórymi nowotworami oraz schorzeniami układu sercowo-naczyniowego,
a ponadto pozytywnie wpływają na układ nerwowy. W zależności od struktury chemicznej wyróżnia się takie podklasy
flawonoidów jak: flawony, flawanony, flawonole, flawanole, antocyjany i izoflawony. Przypuszcza się, że mechanizm
działania tych substancji opiera się na ich silnych właściwościach antyoksydacyjnych oraz innych mechanizmach, takich
jak zdolność do modulowania licznych szlaków enzymatycznych. W wielu badaniach wykazano ich korzystne działanie w
prewencji chorób przewlekłych. Jednakże poznanie dokładnego metabolizmu tych substancji wymaga prowadzenia dalszych
badań. Źródłami flawonoidów w diecie człowieka są warzywa, owoce, orzechy i nasiona, a także niektóre przyprawy. Spo-
żywanie tych substancji wraz z dietą człowieka wydaje się być bezpieczne. Uzasadnionym zatem wydaje się promowanie
diety bogatej we flawonoidy.
Słowa kluczowe: flawonoidy, nowotwory, choroby sercowo-naczyniowe, choroby neurodegeneracyjne
INTRODUCTION
Flavonoids are a diverse group of plant metabolites
with over 10,000 compounds that have been identified
until now. However, only very few of them have been
investigated in detail [25]. They have several important
functions in plants, such as providing protection against
harmful UV radiation or plant pigmentation. In addition,
they have antioxidant, antiviral and antibacterial proper-
ties. They also regulate gene expression and modulate
enzymatic action [25]. All naturally occurring flavono-
ids possess three hydroxyl groups, two of which are on
the ring A at positions five and seven, and one is located
on the ring B, position three. Biochemical actions of
flavonoids depend on the presence and position of va-
rious substituent groups, that affect metabolism of each
compound. They can be found in free or bound forms:
aglycones or β-glycosides [17]. The flavonoid subc-
lasses, based on types of chemical structure, include:
flavonols, flavones, flavanones, flavanols, anthocyanins
and isoflavones [17, 20]. Table 1 shows some common
examples according to this classification.
Antioxidant properties of foodstuffs depend not only
on polyphenol content, but also on their type. For in-
stance, quercetin and catechin demonstrate the greatest
antioxidant properties in vitro [6, 11, 36]. However, their

A. Kozłowska, D. Szostak-Węgierek
80 Nr 2
human metabolism is incompletely understood. Current
studies on biological effects of flavonoids focuse on
their absorption mechanisms, metabolism and bioava-
ilability. Thus, in order to elucidate their physiological
role, molecular studies are required. The results would
enable to evaluate their effectiveness in the treatment
and prevention of certain diseases, together with even-
tual risks arising from their use [18, 33].
FLAVONOIDS CONSUMPTION AND
SAFETY
At present, consumption of dietary flavonoids is
regarded as safe. Nevertheless, it is worth noting that the
use of pharmaceutical products that contain high doses
of bioactive substances is increasing. Such supplements
provide an alternative source of flavonoids to those ob-
tained from the diet. It is of concern that the toxicity of
concentrated sources of flavonoids is unknown, together
with their interactions with other dietary components or
taken medications [12]. Administration of large doses of
a single flavonoid may decrease bioavailability of trace
elements, vitamins or folic acid. Besides, it may exert
an adverse effect on the thyroid function [12]. There is
a special concern about possible side effects of taking
several flavonoid-containing products at the same time
as flavonoid-flavonoid interactions are little known so
far [12]. A consumer may be misled that flavonoids are
entirely safe because they are so-called ’natural’ pro-
ducts. Uncontrolled use of pharmaceutical preparations
containing flavonoids may come out disadvantageous
for health. Furthermore, the packaging labels for some
dietary supplements have scant information about sa-
fety, adverse reactions, interactions, contraindications,
and efficacy [7, 12].
It is clear that the molecular mechanisms of action
of flavonoids need to be thoroughly understood and
intensive research on this problem should be performed.
However, it should be emphasised that in the light of
recent findings the best and safest source of these sub-
stances is a properly balanced diet.
DIETARY CONSUMPTION AND SOURCES
OF FLAVONOIDS
It is estimated that inhabitants of the Western Europe
consume on average 100 – 1000 mg flavonoids/day/
person [17, 36]. This was confirmed by the European
Prospective Investigation into Cancer and Nutrition
(EPIC) study, which showed the median daily intake
of flavonoids in Greek and Spaniard subjects equal
to 93 mg (n ≥ 28,000) and 126.1 mg (n = 40,683) per
Table 1. Subclasses of flavonoids; authors’ selection based
on [17]
Subclass Examples of compounds
Flavonols Quercetin, kaempferol, myricetin
Flavones Luteolin, apigenin, tangeretin
Flavanones Naringenin, hesperetin
Flavanols, Catechin, epicatechin, epigallocatechin,
glausan-3-epicatechin, proanthocyanidins
Anthocyanins Cyanidin, delphinidin, pelargonidin, malvidin
Isoavones Genistein, daidzein
Table 2. Content of flavonoids, according to their sub-
-classes, in chosen foodstuffs (mg/100g foodstuff);
authors’ selection based on [2]
Flavanones Flavones
Artichokes 12.51 Kohlrabi 1.3
Grapefruit juice 18.98 Red grapes 1.3
Orange juice 18.99 Lemons 1.9
Oranges 42.57 Chicory 2.85
Limes 46.40 Celeriac 3.90
Lemons 49.81 Green pepper 4.71
Grapefruit 54.50 Artichokes 9.69
Dried oregano 412.13 Fresh parsley 216.15
Dried oregano 1046.46
Dried parsley 4523.25
Flavonols Anthocyanins
Apples Mean
3.40 Hazel nuts 6.71
Cooked brussel sprouts 5.24 Morello cherries 7.45
Fresh gs 5.47 Pears 12.18
Dried & sweetened
cranberries 6.91 Black grapes 21.63
Buckwheat 7.09 Red table wine 23.18
Chicory 8.94 Pecan nuts 25.02
Morello cherries 9.41 Strawberries 27.76
American bilberries 10.59 Red bilberries 40.15
Blackcurrants 11.53 Raspberries 40.63
Cooked asparagus 15.16 Red cabbage 63.50
Fresh cranberries 21.59 Red currants 75.02
Goji berries 31.20 Blackberries 90.64
Red onions 38.34 American
bilberries 141.03
Rocket lettuce 69.27 Black currants 154.77
Radish 78.09 Chickpeas 262.49
Sorrel 102.20 Bilberries 285.21
Elderberry juice
concentrate 108.16 Aronia 349.79
Dried parsley 331.24 Elderberry juice
concentrate 411.4
Fresh capers 493.03
Flavanols
Apple juice 5.96 Cooked broad
beans 20.63
Apricots 8.41 Blackberries 42.5
Peaches 8.6 Cocoa, dry powder 52.73
Apples 9.17 Dark chocolate 108.60
Red table wine 11.05 Black tea, brewed 115.57
Pecan nuts 15.99 Green tea, brewed 116.15

Flavonoids – food sources and health benefits 81Nr 2
person respectively [9, 39]. The Greek survey was
performed in 1992 – 1996 and thus the results may be
underestimated as the database concerning flavonoid
levels in foodstuffs was incomplete that time. On the
other hand, it is assumed that inhabitants of countries
in the Far East, such as Japan, because of high intake
of legumes, soy and tea, may consume up to 2 g of
flavonoids daily [36]. In contrast, the Polish National
Multi-centre Health Survey (WOBASZ) demonstrated
that the mean flavonoid intake in the Polish population
was 1 g/person/day [41].
Important dietary sources of flavonoids are vege-
tables, fruits, seeds, some cereals, together with wine,
tea and certain spices. Table 2 demonstrates flavonoid
content in chosen foodstuffs. It should be noted that
the presence of particular flavonoids in vegetables and
fruits depends on the crop variety, location and type of
cultivation, as well as the specific plant morphological
part [13]. Differences in flavonoid contents between
varieties of species are usually small, although in a
few cases very high amounts have been observed, e.g.
in certain berries and tea prepared from leaves of the
Quingmao tree [2].
EFFECTS OF FLAVONOIDS ON THE
CARDIOVASCULAR SYSTEM
The well recognised anti-oxidant properties of
flavonoids resulted in the interest about their potential
role in prevention of cardiovascular diseases [18]. For
example, a recent study clearly showed health benefits
of dietary flavonoids as there was a positive association
between their intake and reduction of the risk of car-
diovascular death in adult Americans [22]. The study
demonstrated that both male and female subjects who
consume large amounts of flavonoids (the top quintile)
had the 18% lower mortality risk of cardiovascular di-
seases (CVD) compared to those whose intake was in
the lowest quintile. Another study [3] demonstrated that
high flavonoid consumption (flavones and flavanols)
protected against hypertension. Subjects whose intake of
these substances was in the top quintile, in comparison
with those of the lowest consumption, exhibited the
8% risk reduction of development of this condition [3].
Atherosclerosis is a multifactorial disease. High
blood concentration of oxidatively modified low den-
sity lipoproteins (ox-LDL) accelerates its development.
Other causative factors include blood vessel inflamma-
tion and disorders of coagulation [18, 31]. Because of
their antioxidant and chelating properties, flavonoids
inactivate reactive oxygen species (ROS) and this
way counteract plasma LDL oxidation and ameliorate
inflammation of the blood vessel endothelium. Further-
more, flavonoids decrease activity of xanthine oxidase,
NADPH oxidase, and lipoxygenase ie. the enzymes that
increase ROS production. Anti-arteriosclerotic action of
flavonoids is related also to the reduction of inflamma-
tion in the blood vessel wall through inhibition of the
influx of leucocytes. Flavonoids also decrease activity
of such enzymes as 15-lipoxygenase (15-LOX) and
cyclooxygenase (COX, particularly COX-2). These
enzymes participate in formation of, prostaglandins
and leukotrienes, substances that mediate inflamma-
tion, from arachidonic acid. Decline in their secretion
results in reduction of synthesis of prostaglandin PGE2,
leukotriene B4 and thromboxane A2, what in turn leads
to decrease in inflammation and platelet aggregation.
Inhibition of these enzymes results also in protection of
LDL against oxidation and regulates capillary pressure
back to normal [18].
Beyond of protection of blood vessels against ox-
-LDL, antiatheromatous action of flavonoids results also
from suppression of 3-hydroxy-3-methylglutaryl-coen-
zyme A reductase (HMG-CoA) activity. This enzyme
plays a key role in the synthesis of cholesterol in the
human body, and thereby influences its plasma levels.
Inhibition of its activity lowers intracellular cholesterol
concentrations and results in the following increase in
expression of LDL receptors. This in turn raises the
cellular lipoprotein uptake and removal of cholesterol
from the circulation. Hesperetin is a good example of a
flavonoid, found in lemons and oranges, which reduces
blood cholesterol level in the aforementioned way [18].
Furthermore, a randomised, double-blind study, that
included cell culture, demonstrated in subjects with
metabolic syndrome that oral administration of 500 mg
of hesperetin daily over 3 weeks stimulated endothelial
nitric oxide (NO) formation, what was probably related
to the decreased activity of proinflammatory cytokines.
This study showed that a three week hesperetin sup-
plementation improves endothelial function, reduces
inflammation and beneficially affects lipid profile in
patients with metabolic syndrome [27].
It was shown that such flavonoids as rutin and its
derivatives, along with hesperetin, help seal and rein-
force blood vessel walls [18, 23]. These substances,
similarly to vitamin C, enhance collagen synthesis and
thus make the connective tissue in blood vessels more
elastic. Rutin and its derivatives are used as a medica-
tion aimed at regulation of capillary permeability and
improvement of peripheral circulation [23]. Flavonoids,
such as quercetin or rutin, have anti-aggregating pro-
perties, and thereby reduce the risk of clot formation
near the damaged endothelium [18]. By interaction with
platelet integrins, these substances prevent platelets
from sticking. They also stimulate NO formation in the
vascular endothelium what facilitates vasodilation, and
thus plays a key role in regulation of blood pressure [18].

A. Kozłowska, D. Szostak-Węgierek
82 Nr 2
Obesity is an important and independent risk factor
for CVD and is strongly associated with dyslipidaemia,
insulin resistance and type 2 diabetes [29]. Research on
the effects of long-term flavonoid dietary supplementa-
tion in obese or normal body mass mice, in comparison
with diet without addition of these substances, showed
improved lipid profile, decreased insulin resistance and
reduced visceral adipose tissue mass. The non-obese
mice that consumed flavonoids demonstrated reduced
levels of atherogenic cholesterol fractions (non-HDL
cholesterol) [29]. These findings confirm the protective
effects of flavonoids on the cardiovascular system.
EFFECTS OF FLAVONOIDS ON THE
NERVOUS SYSTEM
Effectiveness of flavonoids in prevention of age-
-related neurodegenerative diseases has been much
investigated in the recent years. It concerns particularly
dementia, Parkinson’s and Alzheimer’s diseases. It se-
ems that flavonoids can modulate neuronal function [21,
26, 34, 38]. Diets rich in these substances were shown
to beneficially affect maintenance of human cognitive
functions, probably through protection of neurons,
enhancement of their function and regeneration [38].
Reactive oxygen and nitrogen species are involved in
the development of many neurodegenerative diseases,
whilst dietary flavonoids have been shown to counteract
effectively oxidative neuronal damage.
It was demonstrated that use of the extract from
the gingobiloba plant, that is rich in flavonoids, may
beneficially influence treatment of the age-related
dementia and Alzheimer’s disease [1]. Tangeretin, a
flavonoid that belongs to the flavone subclass, found
mainly in citrus fruits, was shown to provide protection
in Parkinson’s disease. Animal models of this condition
is based on striatal damage by the neurotoxic substance
6-hydroxydopamine, what in turn leads to damage of the
nigrostriatal pathway that connects the substantia nigra
with the striatum. The latter is responsible, amongst
others, for planning of body movements. Damage of
this area underlies Parkinson’s disease. It was shown
that tangeretin given to mice passes the blood-brain
barrier (BBB) and protects the nigrostriatal pathway
against adverse effects of 6-hydroxydopamine [8].
The PAQUID study (Personnes Age’es QUID), pu-
blished in 2007, convincingly demonstrated that dietary
flavonoids in the elderly support their cognitive functions
[16]. The 10 years long observation was performed in
1640 subjects aged above 65 years, free from dementia
at baseline. The data about flavonoid consumption were
obtained by means of a food frequency questionnaire
that listed foodstuffs containing these substances. At
each visit (four times) every subject underwent cogni-
tive tests including Mini-Mental State Examination,
Benton’s Visual Retention Test and the ‘Isaacs’ Set
Test. Participants whose flavonoid intake was in the
two highest quartiles (ie. above 13.6 mg/day) had better
cognitive function after 10 years than those who consu-
med less of these compounds. Moreover, subjects who
ingested the least amounts of flavonoids (below 10.38
mg/day), lost on average 2.1 points in the Mini-Mental
State Examination scale, while those with the highest
consumption (above 17.7 mg/day) lost only 1.2 points.
These findings demonstrated that regular consumption
of dietary flavonoids exerts beneficial effect on cognitive
function maintenance during aging [16].
The multitude of effects resulting from consum-
ing flavonoids, both with foodstuffs and concentrated
sources, appears to be related to two parallel processes.
The first is regulation of the neuronal signal cascade
what results in the inhibition of cell apoptosis that is
caused by the action of neurotoxic substances. This
promotes neuronal survival and differentiation [34].
Secondly, flavonoids seem to exert beneficial effects on
the peripheral and central nervous systems by generation
of changes in the cerebral blood flow. This can induce
angiogenesis and growth of new nerve cells in the hip-
pocampus. These processes are important for mainte-
nance of neuronal and cognitive brain functions [34].
It seems that regular consumption of foods rich in
flavonoids reduces the risk of neurodegenerative dis-
eases and counteracts or delays the onset of age-related
cognitive disorders. However, mechanisms of flavonoid
action are not entirely clear. The question then arises as
to when to use these substances to ensure their optimal
effectiveness and which of them produce the strongest
protection of the nervous system. Further studies on
this wide group of compounds are therefore necessary
to provide satisfactory answers to these questions.
ANTICANCER ACTION OF FLAVONOIDS
Chemoprevention is defined as the use of natural or
synthetic substances to inhibit or reverse carcinogene-
sis [24]. Much attention, in this respect, is focused on
flavonoids [4, 5, 10, 14, 19, 28, 35]. Epidemiological
and clinical studies suggest that these compounds can
prevent cancer through their interaction with various
genes and enzymes [4]. It seems that biologically active
substances found in foodstuffs may affect such stages of
carcinogenesis as initiation, promotion and progression
[24]. Many mechanisms of flavonoid action have been
discovered. In the initiation and promotion stages, they
include: inactivation of the carcinogen, inhibition of cell
proliferation, enhancement of DNA repair processes,
and reduction of oxidative stress. In the progression
phase flavonoids may induce apoptosis, inhibit angio-

Flavonoids – food sources and health benefits 83Nr 2
genesis, exhibit antioxidant activity, and also cytotoxic
or cytostatic action against cancer cells [4, 19, 24, 40].
Prevention of metabolic activation of procarcino-
gens is related to flavonoid interaction with phase I
enzymes that are responsible for metabolism of various
endogenous or exogenous substrates. This results from
inhibition of the cytochrome P450 enzymes, such as
CYP1A1 and CYP1A2. Flavonoids thus protect against
cellular damage arising from the activation of carcinoge-
nic factors. Another mechanism of their action is related
to reinforcement of mutagen detoxification through
induction of the phase II enzymes, such as glutathione
S-transferase (GST) and UDP-glucuronyl transferase
(UDP-GT), which detoxify and eliminate carcinogens
from the body [4, 15].
The anticancer effects of flavonoids can also be
explained by the cell cycle inhibition. There are two
classes of regulatory molecules responsible for cell
cycle progression: cyclins and cyclin-dependent kina-
ses (CDKs), which are activated under the influence
of mitogenic signals within the cell. The uncontrolled
activation of CDKs plays a key role in the pathoge-
nesis of cancer. Various types of cancer are linked to
excessive CDKs activity through gene mutation. For
this reason, much research is increasingly focused on
substances that can inhibit or modulate CDKs. These
actions may exhibited by such flavonoids as: genistein,
quercetin, daidzein, luteolin, kaempferol, apigenin, and
epigallocatechin.
Current evidence about the anticarcinogenic po-
tential of flavonoids are however still equivocal. Some
studies, that were performed in animals or various cell
models, indicate that certain flavonoids may inhibit both
cancer initiation and progression [10, 30, 37]. However,
experiments on rats, conducted to determine the effect of
tangeretin and quercetin on the risk of cancer occurrence
arising from alphatoxin B1 induction (initiation and
promotion of hepatic cancer) showed that whereas tan-
geretin administrated during tumour initiation reduced
the number of precancerous lesions, quercetin did not
exhibit such effect [30]. Another study showed that the
development of lung cancer in mice exposed to tobacco
smoke was arrested by consumption of both black and
green teas. The results demonstrated that catechins con-
tained in tea may protect against development of cancer
[37]. A further research that tested influence of selected
compounds on cultured human liver cells demonstrated
that luteolin and apigenin also provided effective pro-
tection against cancer development. These flavonoids
seem to inhibit CDKs. However, other studies indicate
that flavonoids have weaker actions in vivo compared
to that in vitro [11, 32]. An investigation on whether
quercetin prevents lung cancer in mice showed that this
substance, in spite of its strong biological activity, is
not absorbed by these animals efficiently enough. The
authors however suggest that further work should be
focused on making the absorption mechanism of this
substance more effective what would probably promote
the expected anticancer action [32].
The studies quoted above were performed in ani-
mals, and so the conclusions should be extrapolated to
humans with caution. Observational studies conducted
on various human populations are also equivocal [10,
14, 35]. The Iowa Women’s Health Study investigated
the effect of dietary flavonoid consumption on the inci-
dence of cancer of the lung, colon, breast and pancreas
in 34,708 post-menopausal women who were observed
in 1986 – 2004. Their dietary habits were determined by
means of a food frequency questionnaire. Results sho-
wed that regular flavonoid consumption significantly
reduced the risk of the lung cancer, particularly in the
women who had stopped smoking. However, there was
no evident effect of flavonoid consumption on the risk
of other cancers [5]. Another study, performed in 34,408
women (aged above 45 years), demonstrated no signi-
ficant link between intake of foods rich in flavonoids
and the risk of cancer [35]. Despite of these findings,
a meta-analysis of 12 studies showed a reduced risk of
breast cancer in women, especially postmenopausal,
who consumed large amounts of flavonoids, such as fla-
vonols and flavones [14]. Further studies are therefore
required to assess the promising influence of flavonoids
on the human body.
SUMMARY
Flavonoids exhibit manifold effects in protection of
the human body. However, the underlying mechanisms
are still not fully understood. According to current
knowledge, a diet that includes flavonoid containing
products should be promoted. Among foods that pro-
vide large amounts of these substances there are: citrus
fruits, blueberries, blackberries, onions, peppers, a
variety of teas, and also oregano and parsley. However,
it should be emphesized that toxicity of flavonoids con-
sumed in large doses remains unknown. For this reason,
use of their dietary supplements should be considered
with caution. The question arises as to when to use these
substances to enable their most effective action, and as
to which flavonoids are the most beneficial to human
health. It is presumed that flavonoids exert stronger
effects in vitro than in vivo, and thus it is important to
determine their mechanisms of action at the molecular
level. Further studies in this area are therefore greatly
needed.
Acknowledgement
This paper was financed by the Warsaw Medical Uni-
versity, Poland

A. Kozłowska, D. Szostak-Węgierek
84 Nr 2
Conflict of interest
The authors declare no conflict of interest.
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Received: 07.11.2013
Accepted: 12.03.2014